Original Journal Article by Sofianopoulou E, Kaptoge SK, Afzal S, et al. - In stratified Mendelian randomization analyses, a causal association between 25-hydroxyvitamin D [25(OH)D] levels and mortality was suggested for people with low vitamin D status.

• Generally, null findings have been documented in randomized trials of vitamin D supplementation for cardiovascular disease and all-cause mortality, but generalizability of findings to persons with low vitamin D status is not clear.

• By performing observational (33 prospective studies with 500,962 people) and Mendelian randomization (four population-based cohort studies with 386,406 middle-aged people of European ancestries) analyses, the dose-response links between 25[OH]D levels and risk of coronary heart disease, stroke, and all-cause mortality were examined.

• Observational analyses revealed inverse links between incident coronary heart disease, stroke, and all-cause death outcomes with 25(OH)D level at low 25(OH)D concentrations.

• Genetically-predicted 25(OH)D was not related to coronary heart disease, stroke, or all-cause mortality, in population-wide genetic analyses.

• However, for those with vitamin D deficiency (25[OH]D level <25 nmol/L), strong evidence from genetic analyses supported an inverse link with all-cause death (odds ratio [OR] per 10 nmol/L rise in genetically-predicted 25[OH]D level 0·69) and non-significant inverse links for stroke (0·85) and coronary heart disease (0·89).

• On attempting a finer stratification of participants, inverse links were identified between genetically-predicted 25(OH)D levels and all-cause death up to around 40 nmol/L.